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Polly J. Ferguson - One of the best experts on this subject based on the ideXlab platform.
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Autoinflammatory diseases affecting bone and joints, and autoinflammatory interferonopathies
Stiehm's Immune Deficiencies, 2020Co-Authors: Polly J. Ferguson, Adriana A. Jesus, Raphaela Goldbach-manskyAbstract:Abstract Autoinflammatory disorders are innate immune system activation disorders. Individuals with autoinflammatory disorders classically have episodes of sterile inflammation that occur in the absence of high-titer autoantibodies and autoreactive T cells, making them distinct from autoimmune disorders. This chapter focuses on autoinflammatory disorders that primarily affect the bone and/or joints including CRMO, DIRA, Majeed Syndrome, PAPA Syndrome, Blau Syndrome, the Behcet's like disease HA20 (haploinsufficiency of A20) and on a subgroup of autoinflammatory interferonopathies including CANDLE/PRAAS, SAVI and COPA. These disorders often are associated with inflammation in a disease-specific manner. The genetic basis for these disorders is becoming increasingly recognized. The pathogenic mechanisms informed by these monogenic defects allow targeted therapy of the enhanced proinflammatory responses in these conditions.
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Genetic Causes of Inflammatory Bone Disease
Textbook of Autoinflammation, 2019Co-Authors: James W. Verbsky, Polly J. FergusonAbstract:This chapter focuses on monogenic autoinflammatory disorders that affect bone. The presence of sterile bone inflammation may be accompanied by inflammation of the skin and intestinal tract. The pathophysiology varies by Syndrome and includes dysregulation of the IL-1 pathway or aberrant intracellular signaling defects leading to activation of innate immune cells including osteoclasts. These are rare disorders with variable outcomes. IL-1 inhibitors have been used successfully to decrease inflammation in Majeed Syndrome, deficiency of the interleukin receptor antagonist and for non-osseous manifestations of neonatal onset multisystem inflammatory disease. For other disorders such as cherubism, treatment remains challenging. Recognition of additional monogenic autoinflammatory is likely as this is a very new field of investigation.
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correction recessive coding and regulatory mutations in fblim1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis crmo
PLOS ONE, 2017Co-Authors: Benjamin W Darbro, Xinyu Bing, Ronald M Laxer, Gabriel Velez, Alexis L Finer, Albert Erives, Vinit B Mahajan, Alexander G Bassuk, Polly J. FergusonAbstract:Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed Syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.
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Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO).
PloS one, 2017Co-Authors: Allison Cox, Xinyu Bing, Benjamin W Darbro, Ronald M Laxer, Gabriel Velez, Alexis L Finer, Albert Erives, Vinit B Mahajan, Alexander G Bassuk, Polly J. FergusonAbstract:Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed Syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.
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Phenotypic Variability in Majeed Syndrome
The Journal of rheumatology, 2016Co-Authors: Anand Prahalad Rao, Dharmanand Balebail Gopalakrishna, Xinyu Bing, Polly J. FergusonAbstract:To the Editor: Majeed Syndrome (OMIM #609628) is a syndromic form of chronic recurrent multifocal osteomyelitis (CRMO) that presents with early onset, severe CRMO, and a microcytic dyserythropoietic anemia of variable severity. Onset in all reported cases has been in the first 2 years of life1,2,3. A minority of patients develop a neutrophilic dermatosis. The disease is due to mutations in LPIN2 , which encodes LIPIN2, a phosphatidate phosphatase important in lipid metabolism2,3,4,5,6. Here we present the case histories of 2 male cousins of Indian heritage with Majeed Syndrome. Both born to parents with consanguineous marriages, the proband presented with typical Majeed Syndrome (onset of CRMO by 2 yrs of age, significant microcytic dyserythropoietic anemia, and failure to thrive), but the cousin had later onset, milder disease more reminiscent of nonsyndromic CRMO (onset at 8 yrs of age and minimal anemia). Both were found to be homozygous for the same novel LPIN2 mutation. Our report details the natural history of the disease in these 2 boys, expands the at-risk ethnic and racial group of Majeed Syndrome, and demonstrates that the disease can present … Address correspondence to Dr. P.J. Ferguson, Department of Pediatrics, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. E-mail: polly-ferguson{at}uiowa.edu
Xinyu Bing - One of the best experts on this subject based on the ideXlab platform.
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correction recessive coding and regulatory mutations in fblim1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis crmo
PLOS ONE, 2017Co-Authors: Benjamin W Darbro, Xinyu Bing, Ronald M Laxer, Gabriel Velez, Alexis L Finer, Albert Erives, Vinit B Mahajan, Alexander G Bassuk, Polly J. FergusonAbstract:Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed Syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.
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Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO).
PloS one, 2017Co-Authors: Allison Cox, Xinyu Bing, Benjamin W Darbro, Ronald M Laxer, Gabriel Velez, Alexis L Finer, Albert Erives, Vinit B Mahajan, Alexander G Bassuk, Polly J. FergusonAbstract:Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed Syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.
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Phenotypic Variability in Majeed Syndrome
The Journal of rheumatology, 2016Co-Authors: Anand Prahalad Rao, Dharmanand Balebail Gopalakrishna, Xinyu Bing, Polly J. FergusonAbstract:To the Editor: Majeed Syndrome (OMIM #609628) is a syndromic form of chronic recurrent multifocal osteomyelitis (CRMO) that presents with early onset, severe CRMO, and a microcytic dyserythropoietic anemia of variable severity. Onset in all reported cases has been in the first 2 years of life1,2,3. A minority of patients develop a neutrophilic dermatosis. The disease is due to mutations in LPIN2 , which encodes LIPIN2, a phosphatidate phosphatase important in lipid metabolism2,3,4,5,6. Here we present the case histories of 2 male cousins of Indian heritage with Majeed Syndrome. Both born to parents with consanguineous marriages, the proband presented with typical Majeed Syndrome (onset of CRMO by 2 yrs of age, significant microcytic dyserythropoietic anemia, and failure to thrive), but the cousin had later onset, milder disease more reminiscent of nonsyndromic CRMO (onset at 8 yrs of age and minimal anemia). Both were found to be homozygous for the same novel LPIN2 mutation. Our report details the natural history of the disease in these 2 boys, expands the at-risk ethnic and racial group of Majeed Syndrome, and demonstrates that the disease can present … Address correspondence to Dr. P.J. Ferguson, Department of Pediatrics, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. E-mail: polly-ferguson{at}uiowa.edu
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Efficacy of anti-IL-1 treatment in Majeed Syndrome
Annals of the rheumatic diseases, 2012Co-Authors: Troels Herlin, Xinyu Bing, Bente Fiirgaard, Mette Bjerre, Gitte Kerndrup, Henrik Hasle, Polly J. FergusonAbstract:Background and objective Majeed Syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2 . Long-term outcome is poor. This is the first report detailing the treatment of Majeed Syndrome with biological agents and demonstrates clinical improvement with IL-1blockade. Methods We describe the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in two brothers with Majeed Syndrome. Results Both boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis. Their bone disease and anaemia were refractory to treatment with corticosteroids. Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no improvement. IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or an anti-IL-1β antibody (canakinumab) resulted in dramatic clinical and laboratory improvement. Conclusions The differential response to treatment with TNF-α or IL-1 blocking agents sheds light into disease pathogenesis; it supports the hypothesis that Majeed Syndrome is an IL-1β dependent autoinflammatory disorder, and further underscores the importance of IL-1 in sterile bone inflammation.
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Correspondence to
2012Co-Authors: Xinyu Bing, Polly J. Ferguson, Clinical Genetics DepartmentAbstract:Background and objective Majeed Syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2. Long-term outcome is poor. This is the first report detailing the treatment of Majeed Syndrome with biological agents and demonstrates clinical improvement with IL-1blockade. Methods We describe the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in two brothers with Majeed Syndrome. Results Both boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis. Their bon
Hatem El-shanti - One of the best experts on this subject based on the ideXlab platform.
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Characterization of the LPIN2 Gene and its Protein and Examination of its Role in Psoriasis
2010Co-Authors: Yasmin Walid Abu Aqel, Mazen Osman, Fatma Abdallah, Hanan Abu Nada, Jamil Alami, Hatem El-shantiAbstract:Abstract Psoriasis is a chronic inflammatory skin disease posing a considerable worldwide health problem due to its high prevalence, associated morbidity and high health-care costs. It is a multifactorial “complex” disorder, with compelling evidence for a genetic predisposition. On the other hand, Majeed Syndrome, a Mendelian disorder of bone and skin inflammation is caused by homozygous mutations in LPIN2. Many observations have implicated LPIN2 in the genetic etiology of psoriasis, including its position in a psoriasis locus. We identified several non-synonymous SNPs within the LPIN2 in patients with psoriasis that are not present in healthy controls. We hypothesize that the variations in LPIN2 play a role in the susceptibility to development of psoriasis and that LPIN2 is the psoriasis susceptibility locus on 18p. We aim to examine this hypothesis by examining the properties of the wild type and mutant proteins, as well as examining any difference in function between the wild type and mutants. We have obtained custom synthesized cDNA clones encoding the full Lipin2 wild type protein and the six identified mutant proteins (p.K387E, p.S734L, p.A331S, p.L504F, p.P348L, p.E601K). The cDNA clones were subcloned into pYES2 vector for expression in yeast cells (Saccharomyces cerevisiae). Each construct was transformed into Saccharomyces cerevisiae for protein expression. The analysis utilizes SDS Gel Electophoresis and Western Blot. The DNA analysis indicates that each fragment has been correctly cloned into the pYES2 vector. The analyses using SDS Gel Electrophoresis and Western Blot indicate that the Wild type and p.K387E are successfully expressed in S. cerevisiae while p.S734L is expressed in S. cerevisiae but at a lower level. Expression experiments are being done on the 4 remaining mutant proteins. We were successful in artificially expressing the human Lipin2 protein in its different forms in yeast cells. We are currently optimizing the conditions to produce substantial amounts of the proteins to be studied by Circular dichroism to determine the folding patterns. Other methods will be approached to study the function.
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Chronic recurrent multifocal osteomyelitis: a concise review and genetic update.
Clinical orthopaedics and related research, 2007Co-Authors: Hatem El-shanti, Polly J. FergusonAbstract:Chronic recurrent multifocal osteomyelitis is an autoinflammatory disorder characterized by bone pain and fever, a course of exacerbations and remissions, and a frequent association with other inflammatory conditions. Because its etiology is largely unknown, the diagnosis is still based on clinical criteria; treatment is empiric and not always successful. The diagnosis is supported by the presence of osteolytic lesions with surrounding sclerosis apparent on radiographs, and silent asymptomatic lesions frequently appear on nuclear scans. The histologic findings in bone biopsies are nonspecific, showing inflammatory changes with granulocytic infiltration. Several observations suggest the contribution of genetic factors to the etiology of chronic recurrent multifocal osteomyelitis. Indeed, mutations in LPIN2 cause a syndromic form of chronic recurrent multifocal osteomyelitis known as Majeed Syndrome, while mutations in pstpip2 cause a murine form of the disorder. The roles played by LPIN2 and the human homolog of pstpip2, PSTPIP2, in the etiology of chronic recurrent multifocal osteomyelitis are uncertain but are currently being investigated. We emphasize the need to validate diagnostic clinical criteria and develop new pathogenesis-based targeted therapy.
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Autoinflammatory bone disorders.
Current opinion in rheumatology, 2007Co-Authors: Polly J. Ferguson, Hatem El-shantiAbstract:Purpose of review This review provides an update on clinical, genetic, and immunologic aspects of the autoinflammatory bone disorders. Recent findings Chronic noninfectious inflammation of the bone is a clinical feature of both chronic recurrent multifocal osteomyelitis and (to a lesser degree) cherubism. The genes responsible for Majeed Syndrome (LPIN2), murine chronic multifocal osteomyelitis (pstpip2), and cherubism (SH3BP2 and possibly PTPN11) have been identified. Murine models of both chronic recurrent multifocal osteomyelitis and cherubism have demonstrated that the bone inflammation is mediated by hematopoietically derived cells and can occur in the absence of a functioning adaptive immune system. As the immunologic defects become better defined, the cells of the myeloid lineage are emerging as the primary players. Summary Chronic multifocal osteomyelitis and cherubism are hereditary chronic inflammatory disorders in which bone is the primary inflammatory target. Recent genetic and immunologic discoveries demonstrate involvement of the innate immune system, which places these entities in the category of autoinflammatory disorders.
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Majeed Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
1993Co-Authors: Hatem El-shanti, Polly J. FergusonAbstract:NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE. Clinical characteristics Majeed Syndrome is characterized by: Some individuals also develop a transient inflammatory dermatosis, often manifesting as Sweet Syndrome (neutrophilic skin infiltration). Diagnosis/testing The diagnosis is based on clinical findings and molecular genetic testing of LPIN2, the only gene in which pathogenic variants are known to cause Majeed Syndrome. Management Treatment of manifestations: CRMO is treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy to avoid disuse atrophy of muscles and contractures. If CRMO does not respond to NSAIDs, corticosteroids can be used short term to control CRMO and skin manifestations; however, the complications of long-term use of corticosteroids limit their use in children. Two affected children had resolution of their bone inflammation when treated with an IL-1 inhibitor. Physical therapy should be employed to avoid disuse atrophy of muscles or contractures. CDA is treated with red blood cell transfusion if indicated. Surveillance: Routine complete blood count (CBC) to determine if red blood cell transfusion is necessary. Agents/circumstances to avoid: Prolonged bed rest. Genetic counseling Majeed Syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants in the family are known. If the pathogenic variants in the family have been identified, prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.
Hatem Elshanti - One of the best experts on this subject based on the ideXlab platform.
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a splice site mutation confirms the role of lpin2 in Majeed Syndrome
Arthritis & Rheumatism, 2007Co-Authors: Zakiya Almosawi, Khulood K Alsaad, Roya Ijadimaghsoodi, Hatem Elshanti, Polly J. FergusonAbstract:Majeed Syndrome is an autoinflammatory disorder consisting of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis. To date, 2 unrelated families with Majeed Syndrome have been reported. Mutations in LPIN2 have been found in both families. Here we report a third consanguineous family with Majeed Syndrome with a novel mutation. The patient, a 3-year-old Arabic girl, had hepatosplenomegaly and anemia as a neonate. At age 15 months, she developed recurrent episodes of fever and multifocal osteomyelitis. In addition, bone marrow aspiration demonstrated significant dyserythropoiesis, suggesting Majeed Syndrome. Coding sequences and splice sites of LPIN2 were sequenced in the patient and her mother. A homozygous single-basepair change was detected in the donor splice site of exon 17 (c.2327+1G>C) in the patient; her mother was heterozygous at this site. These data confirm the role of LPIN2 mutations in the etiology of Majeed Syndrome.
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a missense mutation in pstpip2 is associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis
Bone, 2006Co-Authors: Polly J. Ferguson, Xinyu Bing, Mohammed A Vasef, Luis A Ochoa, Amar Mahgoub, Thomas J Waldschmidt, Lorraine T Tygrett, Annette J Schlueter, Hatem ElshantiAbstract:Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder that primarily affects bone but is often accompanied by inflammation of the skin and/or gastrointestinal tract. The etiology is unknown but evidence suggests a genetic component to disease susceptibility. Although most cases of CRMO are sporadic, there is an autosomal recessive syndromic form of the disease, called Majeed Syndrome, which is due to homozygous mutations in LPIN2. In addition, there is a phenotypically similar mouse, called cmo (chronic multifocal osteomyelitis) in which the disease is inherited as an autosomal recessive disorder. The cmo locus has been mapped to murine chromosome 18. In this report, we describe phenotypic abnormalities in the cmo mouse that include bone, cartilage and skin inflammation. Utilizing a backcross breeding strategy, we refined the cmo locus to a 1.3 Mb region on murine chromosome 18. Within the refined region was the gene pstpip2, which shares significant sequence homology to the PSTPIP1. Mutations in PSTPIP1 have been shown to cause the autoinflammatory disorder PAPA Syndrome (pyogenic arthritis, pyoderma gangrenosum and acne). Mutation analysis, utilizing direct sequencing, revealed a single base pair change c.293T → C in the pstpip2 gene resulting in a highly conserved leucine at amino acid 98 being replaced by a proline (L98P). No other mutations were found in the coding sequence of the remaining genes in the refined interval, although a 50 kb gap remains unexplored. These data suggest that mutations in pstpip2 may be the genetic explanation for the autoinflammatory phenotype seen in the cmo mouse.
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homozygous mutations in lpin2 are responsible for the Syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia Majeed Syndrome
Journal of Medical Genetics, 2005Co-Authors: Polly J. Ferguson, Shan Chen, Marwan K Tayeh, L Ochoa, Suzanne M Leal, Anna Pelet, Arnold Munnich, Stanislas Lyonnet, Hasan Abdel Majeed, Hatem ElshantiAbstract:Background: Majeed Syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed Syndrome causal gene and to speculate on its function and role in skin and bone inflammation. Methods: Six individuals with Majeed Syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed Syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out. Results: The phenotype of Majeed Syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown. Conclusions: We conclude that homozygous mutations in LPIN2 result in Majeed Syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet Syndrome, and psoriasis.
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Majeed Syndrome retired chapter for historical reference only
1993Co-Authors: Hatem Elshanti, Polly J. FergusonAbstract:NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE. Clinical characteristics Majeed Syndrome is characterized by: Some individuals also develop a transient inflammatory dermatosis, often manifesting as Sweet Syndrome (neutrophilic skin infiltration). Diagnosis/testing The diagnosis is based on clinical findings and molecular genetic testing of LPIN2, the only gene in which pathogenic variants are known to cause Majeed Syndrome. Management Treatment of manifestations: CRMO is treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy to avoid disuse atrophy of muscles and contractures. If CRMO does not respond to NSAIDs, corticosteroids can be used short term to control CRMO and skin manifestations; however, the complications of long-term use of corticosteroids limit their use in children. Two affected children had resolution of their bone inflammation when treated with an IL-1 inhibitor. Physical therapy should be employed to avoid disuse atrophy of muscles or contractures. CDA is treated with red blood cell transfusion if indicated. Surveillance: Routine complete blood count (CBC) to determine if red blood cell transfusion is necessary. Agents/circumstances to avoid: Prolonged bed rest. Genetic counseling Majeed Syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants in the family are known. If the pathogenic variants in the family have been identified, prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.
Benjamin W Darbro - One of the best experts on this subject based on the ideXlab platform.
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correction recessive coding and regulatory mutations in fblim1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis crmo
PLOS ONE, 2017Co-Authors: Benjamin W Darbro, Xinyu Bing, Ronald M Laxer, Gabriel Velez, Alexis L Finer, Albert Erives, Vinit B Mahajan, Alexander G Bassuk, Polly J. FergusonAbstract:Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed Syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.
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Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO).
PloS one, 2017Co-Authors: Allison Cox, Xinyu Bing, Benjamin W Darbro, Ronald M Laxer, Gabriel Velez, Alexis L Finer, Albert Erives, Vinit B Mahajan, Alexander G Bassuk, Polly J. FergusonAbstract:Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed Syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.
